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Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones

2008; National Academy of Sciences; Volume: 105; Issue: 35 Linguagem: Inglês

10.1073/pnas.0804773105

1091-6490

Ting‐Chao Chou, Xiu-Guo Zhang, Ziyang Zhong, Yong Li, Li Feng, Sara Eng, David Myles, Robert Johnson, Nian Wu, Ye Ingrid Yin, Rebecca M. Wilson, Samuel J. Danishefsky,

Synthetic Organic Chemistry Methods

The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.